Ca2 channels

Ca2+ channel Dopamine Dj Endothelin ETa Endothelin ETb Histamine H2 Muscarinic ml Muscarinic m2 Muscarinic m3 Muscarinic m4 NE transporter Nicotinic Ach NPY,... 

Antiepileptics Na+, Ca2+ channels GABA receptors l Na+currents l Ca2+ currents GABA receptor activity l Excitability of peripheral and central neurons l Release of excitatory neurotransmitters Sedation, dizziness, cognitive impairment, ataxia, hepatotoxicity, thrombocytopenia... 

Not all cells in the heart express the fast sodium channel. Thus, sinus nodal and atrioventricular nodal cells lack the fast Na+ channel and instead generate their action potentials via opening of Ca2+ channels. This is the basis for their sensitivity to Ca2+ antagonists. 

Quinidine, the classical class IA drug, binds to the open state oftheNa+ channel, and prolongs the action potential by block of the delayed rectifier-. In higher concentrations, L-type Ca2+ channels are inhibited. Quinidine exerts antimuscarinic effects, thereby accelerating AV-nodal... 

Verapamil is a phenylalkylamine which blocks L-type Ca2+ channels in a use-dependent manner. The drug binds to the inactivated state of the channel. Diltiazem is a benzothiazepine derivative with a profile of action most similar to that of verapamil. 

Intravenous administration of magnesium sulfate (1-5 g) is used for the termination of torsade de pointes arrhythmia. The underlying electrophysiological mechanism is not well understood. It includes changes of the current-voltage relationship of Iki and Ca2+ channel blockade. 

The risk of atrial flutter is a 2 1 transmission to the ventricles generating a high ventricular rate. The therapeutic goal is to reduce transmission to 3 1 or 4 1 by administration of either (3-adrenoceptor antagonists, Ca2+ channel blockers or amiodarone. Quinidine must not be used in this arrhythmia, since it accelerates AV-conduction due to its vagolytic effect. 

Voltage-dependent Na+ Channels Voltage-dependent Ca2+ Channels (3-Adrenergic System Cardiac Glycosides... 

Class IV antiarrhythmic drugs are Ca2+ channel blockers, which predominantly slow sinus rate and atrioventricular conduction and thus are used in the treatment of supraventricular tachyarrhythmias. These drugs exert a pronounced negative inotropic effect. 

This synopsis refers only to actions demonstrated within or close to therapeutic concentrations of drugs. Abbreviations (+) to (+++) weak to strong efficacy, (-) no efficacy, ( ) not investigated. HVA high threshold Ca2 channels, T T-type Ca2+ channels, L L-type Ca2+ channels, iNap persistent sodium current, DR delayed rectifier K channels, KCNQ KCNQ subtypes of K+ channels. 

Ionotropic Glutamate Receptors Voltage-dependent Ca2+ Channels Voltage-gated K+ Channels... 

Sorcin (soluble resistance-related calcium binding protein) was isolated from multidrug-resistant cells and is expressed in a few mammalian tissues such as skeletal muscle, heart, and brain. In the heart, sorcin interacts with the ryanodine receptor and L-type Ca2+-channels regulating excitation in contraction coupling. 

An oligomeric protein that spans a cell membrane forming a regulated pore through which Ca2+ can pass. Ca2+ channels differ considerably in their selectivity for Ca2+ over other cations For example DP3R are poorly selective, voltage-dependent Ca2+ channels are vety selective. 

Ca2+ is an important intracellular second messenger that controls cellular functions including muscle contraction in smooth and cardiac muscle. Ca2+ channel blockers inhibit depolarization-induced Ca2+ entry into muscle cells in the cardiovascular system causing a decrease in blood pressure, decreased cardiac contractility, and antiarrhythmic effects. Therefore, these drugs are used clinically to treat hypertension, myocardial ischemia, and cardiac arrhythmias. 

Voltage-gated Ca2+ channels are Ca2+-selective pores in the plasma membrane of electrically excitable cells, such as neurons, muscle cells, (neuro) endocrine cells, and sensory cells. They open in response to membrane depolarization (e.g., an action potential) and permit the influx of Ca2+ along its electrochemical gradient into the cytoplasm. 

Like other voltage-gated cation channels, Ca2+ channels exist in at least three states A resting state stabilized at negative potentials (such as the resting potentials of most electrically excitable cells) that is a closed state from which the channel can open. The open state is induced by depolarization. Channels do not stay open indefinitely because they are turned off during prolonged depolarization by transition into an inactivated state. Inactivation is driven both by depolarization... 

In order to accomplish these diverse physiological tasks described above, nature has created at least five different types of Ca2+ channels. These are termed L-, N-, P/Q-, R-, and T-type. Although they are all structurally similar (Fig. 1) they differ with respect to their biophysical properties. Some of them need only weak depolarizations to open and inactivate fast (e.g., T-type Ca2+ channels), whereas others require strong depolarizations and inactivate more slowly (e.g. P- or L-type Ca2+ channels). Channel types also differ with respect to their sensitivity to drugs. This selectivity is exploited for pharmacotherapy. 

At present, only organic blockers of L-type Ca2+ channels (also termed Ca2+ antagonist ) are licensed... 

Ca2+ Channel Blockers. Figure 1 Most voltage-gated Ca2+ channels exist as a hetero-oligomeric complex of several subunits, a 1 subunits form the Ca2+-selective ion pore and contain the voltage-sensors of the channel. 

In the case of L-type Ca2+ channels, they also carry binding sites for Ca2+ antagonist drugs. The accessory a2-5, p, and y subunits stabilize Ca2+ channel function and support its targeting to the plasma membrane. Notably other proteins can associate with the channel complex allowing the formation of signaling complex important for channel targeting and modulation. 

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